The respiratory muscles, especially the diaphragm, are often required to sustain high levels of contractile effort for prolonged periods. The objectives of this project are first, to examine the relationship between the metabolic behavior of the diaphragm and its endurance; second, to assess the effects on endurance of factors such as acidosis, availability of oxygen and substrate, and alterations of diaphragmatic mechanics; and third, to study the role of respiratory muscle dysfunction in the pathophysiology of acute respiratory failure. For endurance studies, lightly anesthetized dogs will breathe against a severe inspiratory air flow resistance. Diaphragmatic blood flow will be measured by the Kety-Schmidt method; utilization of oxygen, glucose, lactate and FFA will be computed from blood flow and diaphragmatic arterio-venous concentration differences. These measurements will be made at intervals during prolonged resistive work. At the end of the run diaphragm muscle tissue will be assayed for lactate, glycogen and phosphagens. Modifications of the basic protocol include addition of adverse conditions such as hypoxia, acidosis, or creating a mechanical disadvantage for the diaphragm by increasing lung volume; studying potentially beneficial interventions such as hyperoxia and increased availability of substrate; and substituting restrictive for resistant loads. To study the pathogenesis of acute respiratory failure, the state of circulatory, cerebral and respiratory muscle function will be examined while the animals are being stressed with a combination of severe inspiratory resistance and hypoxia. The onset of respiratory muscle failure will be identified by a fall in transdiaphragmatic pressure. The contributions to decreased diaphragmatic contractility of circulatory inadequacy and depressed cerebral function will be assessed from measurements of left ventricular and systemic arterial pressure, cardiac output, myocardial, cerebral and diaphragmatic blood flow, oxygen consumption and tissue metabolites under conditions of spontaneous breathing versus electrophrenic stimulation.